Preclinical Pharmacokinetics and Biodistribution of Anticancer Dinuclear Palladium(II)-Spermine Complex (Pd2Spm) in Mice

Abstract

Palladium-based compounds are regarded as potential analogs to platinum anticancer drugs with improved properties. The present study assessed the pharmacokinetics and biodistribution of a dinuclear palladium(II)-spermine chelate (Pd2Spm), which has previously been shown to possess promising in vitro activity against several therapy-resistant cancers. Using inductively coupled plasma-mass spectrometry, the kinetic profiles of palladium/platinum in serum, serum ultrafiltrate and tissues (kidney, liver, brain, heart, lungs, ovaries, adipose tissue and mammary glands) were studied in healthy female Balb/c mice after a single intraperitoneal bolus injection of Pd2Spm (3 mg/kg bw) or cisplatin (3.5 mg/kg bw) between 0.5 and 48 h post-injection. Palladium in serum exhibited biphasic kinetics with a terminal half-life of 20.7 h, while the free palladium in serum ultrafiltrate showed a higher terminal half-life than platinum (35.5 versus 31.5 h). Palladium was distributed throughout most of the tissues except for the brain, with the highest values in the kidney, followed by the liver, lungs, ovaries, adipose tissue and mammary glands. The in vitro cellular accumulation was also evaluated in breast cancer cells, evidencing a passive diffusion as a mechanism of Pd2Spm’s cellular entry. This study reports, for the first time, the favorable pharmacokinetics and biodistribution of Pd2Spm, which may become a promising pharmacological agent for cancer treatment.

Platinum and Palladium Complexes as Promising Sources for Antitumor Treatments

“…The pharmacokinetic profile and distribution of Pd 2 Spm is advantageous for cancer treatment. This compound induces a much faster metabolic response compared to cisplatin, so that the performance of the tested organs returns to its original state much earlier; thus, patients are expected to recover sooner than with cisplatin treatment [ 47 ].…”

Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice

“…TNBC cells such as MDA-MB-231 cells demonstrated similar antiproliferative effects of Pd 2 Spm and cisplatin [ 11 ], but it was reported that breast cancer cells accumulate approximately four times lower amounts of Pd 2 Spm than cisplatin, i.e., a lower intracellular quantity of Pd 2 Spm is required to produce similar antiproliferative effects. This implies the occurrence of alternative (yet unknown) anticancer molecular target(s) for Pd 2 Spm versus cisplatin [ 15 , 16 , 17 , 18 ]. A recent pharmacokinetic study in mice also showed that while Pd 2 Spm has a very similar serum terminal half-life to cisplatin, it presents a lower accumulation in major organs as compared to cisplatin [ 15 ].…”

“…This implies the occurrence of alternative (yet unknown) anticancer molecular target(s) for Pd 2 Spm versus cisplatin [ 15 , 16 , 17 , 18 ]. A recent pharmacokinetic study in mice also showed that while Pd 2 Spm has a very similar serum terminal half-life to cisplatin, it presents a lower accumulation in major organs as compared to cisplatin [ 15 ]. Therefore, Pd 2 Spm is expected to show a superior tolerability as well as lower nephrotoxicity/hepatotoxicity than cisplatin, owing to both lower tissue accumulation and decreased metabolic reactivity with kidney and liver biomolecules responsible for the associated toxicity (which was recently reported by our group) [ 15 , 19 ].…”

Impact of the Pd2Spm (Spermine) Complex on the Metabolism of Triple-Negative Breast Cancer Tumors of a Xenograft Mouse Model

“…These are important limiting factors that adversely affect treatment outcomes and are mainly correlated with the accumulation of the chemotherapeutics in these organs [ 83 , 84 ]. Our recent comparative pharmacokinetic study in mice revealed a significantly lower accumulation of palladium (from Pd 2 Spm) in the lungs, brain, liver and heart, compared to platinum (from cDDP) [ 73 ]. Therefore, due to its lesser accumulation, Pd 2 Spm is not expected to cause significant deleterious effects (i.e., low cardiotoxicity and hepatotoxicity are expected) compared to cisplatin, thus establishing it as a promising alternative as a putative chemotherapeutic for breast cancer treatment.…”

“…Additionally, the antimetastatic properties of Pd 2 Spm have been demonstrated through its anti-angiogenic and anti-migratory effects [ 72 ]. Moreover, Pd 2 Spm has exhibited favorable pharmacokinetics and biodistribution in healthy mice [ 73 ], thus increasing the interest in this compound as a promising pharmacological agent for cancer treatment. However, the potential cytotoxic effect of Pd 2 Spm needs to be further validated in in vivo cancer models, and this is the subject of ongoing work in our group.…”